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Exploring the Influence of the Aromaticity on the Anticancer and Antivascular Activities of Organoplatinum(II) Complexes
Author(s) -
Zamora Ana,
Pérez Sergio A.,
Rothemund Matthias,
Rodríguez Venancio,
Schobert Rainer,
Janiak Christoph,
Ruiz José
Publication year - 2017
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201700717
Subject(s) - apoptosis , chemistry , cytotoxicity , stereochemistry , cisplatin , cell culture , in vivo , angiogenesis , intracellular , cytotoxic t cell , cancer research , in vitro , biochemistry , biology , chemotherapy , microbiology and biotechnology , genetics
A series of new organometallic Pt II complexes of the type [Pt(C^N)Cl(DMSO)] (C^N= N , N ‐dimethyl‐1‐(2‐aryl)methanamine‐κ 2 C2,N ; aryl=phenyl 2 a , biphenyl 2 b , p ‐terphenyl 2 c , naphthyl 2 d , anthracenyl 2 e , or pyrenyl 2 f ) have been synthesized to explore the influence of the aromaticity on their anticancer activity. The best performers, 2 b and d , are more active than cisplatin (CDDP) in epithelial ovarian carcinoma cells A2780, with 2 d having a higher selectivity factor than CDDP in all the tested cell lines. In addition, all the new compounds overcome the acquired resistance in A2780cisR cells and interestingly, show low micromolar IC 50 values towards the triple negative breast cancer cell line MDA‐MB‐231 and the highly metastatic 518A2 melanoma cells. This study shows that the hydrophobicity, accumulation into cells, and metal levels on nuclear DNA for the complexes are consistent with their cytotoxicity. Complexes 2 b and d induce apoptosis in a caspase‐independent manner and suppress the intracellular ROS generation without modifying the mitochondria membrane potential. In addition, 2 a – f effectively inhibit angiogenesis in the endothelial cell line EA.hy926 at sub‐cytotoxic concentrations and 2 b and d show in vivo antivascular effects on the chorioallantoic membrane (CAM) of fertilized SPF‐eggs (SPF=specific‐pathogen‐free). Inhibition of tubulin polymerization and degeneration of cytoskeleton organization in 518A2 melanoma cells are presented as a preliminary mechanism of its antimetastatic activity.